Dihydroxy (3-pyridyl) borane compounds

ABSTRACT

A dihydroxy(3-pyridyl)borane compound of the formula (1): 
                         
wherein R 1  represents a hydrogen atom, halogen atom or alkoxycarbonylamino group; R 2  represents a hydrogen atom, halogen atom, alkyl group or fluoroalkyl group; with the proviso that the case wherein both R 1  and R 2  are hydrogen atoms is excepted.

TECHNICAL FIELD

The present invention relates to novel dihydroxy(3-pyridyl)boranecompounds and a production method thereof.

BACKGROUND ART

It is described in JP 54-144379A that pyridine compounds having anaromatic hydrocarbyl group or aromatic heterocyclic group at 3-positionare important intermediates for producing medicaments, plant protectantsand so on, and that it is desired to develop a beneficial productionmethod thereof. Further, it is known that some 3-substituted pyridinesare useful for perfume in JP 57-16862A, JP 4-230665A and so on.

DISCLOSURE OF INVENTION

The present invention provides novel dihydroxy(3-pyridyl)boranecompounds of the formula (1) below:

wherein R¹ represents a hydrogen atom, halogen atom oralkoxycarbonylamino group; R² represents a hydrogen atom, halogen atom,alkyl group or fluoroalkyl group; the carbon number of the alkoxy insaid alkoxycarbonylamino group is 1 to 4, and each of the carbon numberof said alkyl group and said fluoroalkyl group is 1 to 4; with theproviso that the case wherein both R¹ and R² are hydrogen atoms isexcepted;which are raw materials for producing 3-substituted pyridine compounds.

The present invention also provides a method for producing thedihydroxy(3-pyridyl)borane compounds of the formula (1).

In the dihydroxy(3-pyridyl)borane compounds of the present invention,examples of the halogen atom for R¹ in the formula (1) include fluorine,chlorine, bromine and iodine. Examples of the alkoxycarbonylamino groupare alkoxycarbonylamino group having C1–C4 straight or branched chainalkoxy group such as methoxycarbonylamino, ethoxycarbonylamino,propoxycarbonylamino, isopropoxycarbonylamino, butoxycarbonylamino andt-butoxycarbonylamino group.

Further, examples of the halogen atom for R² in the formula (1) includefluorine, chlorine, bromine and iodine; examples of the alkyl group areC1–C4 straight or branched chain lower alkyl group such as methyl,ethyl, propyl, isopropyl, butyl and t-butyl group; and examples of thefluoroalkyl group are C1–C4 alkyl group substituted by one or morefluorine atoms for hydrogen atoms such as monofluoromethyl,difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,2-difluoromethyl,1,1,2-trifluoroethyl, 1,1,1,2-tetrafluoroethyl, 1,1,2,2-tetrafluoroethyland 1,1,1,2,2-pentafluoroethyl group.

The dihydroxy(3-pyridyl)borane compounds of the present invention can beproduced by the following method.

The dihydroxy(3-pyridyl)borane compounds of the formula (1) wherein R¹represents a halogen atom or alkoxycarbonylamino group, namely thedihydroxy(2-halogeno-3-pyridyl)borane compounds and thedihydroxy(2-alkoxycarbonylamino-3-pyridyl)borane compounds of theformula (4):

wherein R² represents a hydrogen atom, halogen atom, alkyl group orfluoroalkyl group; R³ represents a halogen atom or alkoxycarbonylaminogroup; the carbon number of said alkyl group and fluoroalkyl group is 1to 4; and the carbon number of the alkoxy in said alkoxycarbonylaminogroup is 1 to 4;can be easily produced by reacting a pyridine compound of the formula(2):

wherein R² and R³ represent the same meanings mentioned above, withlithium amide in an organic solvent, and conducting a reaction by addinga trialkoxyborane compound of the formula (3):B(OR⁴)₃  (3)wherein R⁴ represents a C1–C4 alkyl group,to the reaction mixture, and then reacting the resulted reaction mixturewith water.

The organic solvent is not restricted as long as it is inactive in thereaction. Examples of the organic solvent include ethers such as1,2-dimethoxyethane, diethyl ether and tetrahydrofuran; aliphatichydrocarbons such as hexane, heptane and octane; and mixtures thereof.

Typical examples of the pyridine compound of the formula (2) include2-chloropyridine, 2-bromoropyridine, 2,5-dichloropyridine,2-chloro-6-methylpyridine, 2-chloro-5-trifluoromethylpyridine and2-t-butoxycarbonylaminopyridine.

Typical examples of the lithium amide include lithium dialkylamide suchas lithium diethylamide and lithium diisopropylamide; lithiumpolymethyleneimide such as lithium pyrrolidide and lithium piperidide;and lithium 2,2′,6,6′-tetramethylpiperidide. Among them, lithiumdi(C1–C4 alkyl)amide is preferably used. Said lithium amide is usuallyprepared from a secondary amine and an alkyllithium. Examples of thesecondary amine include dialkylamine such as diethylamine,diisopropylamine; polymethyleneimine such as pyrrolidine and piperidine;and 2,2′,6,6′-tetramethylpiperidine. Examples of the alkyllithiuminclude C1–C4 alkyllithium such as methyllithium and butyllithium;phenyllithium; and naphthyllithium. The lithium amide is preferablyprepared from the secondary amine and the alkyllithium just before thereaction. For example, it can be easily prepared almost quantitativelyby mixing equimolar secondary amine and alkyllithium under stirring inan organic solvent. The pyridine compound of the formula (2) is added tothe prepared lithium amide solution and mixed under stirring, and thereaction mixture is allowed to react with trialkoxyborane compound ofthe formula (3), and subsequently water to give thedihydroxy(2-halogeno-3-pyridyl)borane compound ordihydroxy(2-alkoxycarbonylamino-3-pyridyl)borane compound of the formula(4). In the preparation of lithium amide, the reaction temperature ofthe secondary amine with the alkyllithium is preferably −80 to 0° C.

The reaction temperature of the pyridine compound of the formula (2)with the lithium amide is preferably −80 to −20° C. The amount of thelithium amide used in the reaction is usually between 1.0 and 3.5 molesper 1 mole of the pyridine compound of the formula (2), and the amountof the organic solvent is usually between 1 and 100 parts by weight per1 part by weight of the pyridine compound of the formula (2).

In the trialkoxyborane compound of the formula (3), examples of thealkyl group given by R⁴ in the formula (3) include C1–C3 straight orbranched chain alkyl group, namely, methyl, ethyl, propyl and isopropylgroup, and typical examples of the trialkylborane compound includetrimethoxyborane, triethoxyborane, tripropoxyborane andtriisopropoxyborane. The amount of the trialkoxyborane compound of theformula (3) used in the reaction is usually between 1.0 and 3.5 molesper 1 mole of the pyridine compound of the formula (2). The reactiontemperature of the trialkoxyborane compound of the formula (3) ispreferably −80 to −20° C. as well as the reaction temperature of thepyridine compound of the formula (2) with the lithium amide.

The last reaction with water can be performed by only adding water tothe reaction mixture and stirring well. The amount of the water usedabove is usually between 1 and 10 parts by weight per 1 part by weightof the pyridine compound of the formula (2). The reaction temperature isusually −80 to 50° C., preferably −30 to 30° C.

In the production method, it is thought that a 3-pyridyllithium compoundof the formula (8):

wherein R² and R³ represent the same meanings mentioned above, isproduced by the reaction of the pyridine compound of the formula (2)with the lithium amide. It is thought that said 3-pyridyllithiumcompound reacts with the trialkoxyborane compound of the formula (3) togive a dialkoxy(3-pyridyl)borane compound of the formula (9):

wherein R², R³ and R⁴ represent the same meanings mentioned above, andfurther that the obtained dialkoxy(3-pyridyl)borane compound ishydrolyzed to give the dihydroxy(2-halogeno-3-pyridyl)borane compound ordihydroxy(2-alkoxycarbonylamino-3-pyridyl)borane compound.

It is preferable to keep the reaction mixture being in anhydrouscondition, because the alkyllithium, lithium amide and 3-pyridyllithiumcompound of the formula (8) tend to react with water to decomposeeasily. For example, it is preferable to use the organic solvent welldried for the reaction.

In the novel dihydroxy(3-pyridyl)borane compounds of the formula (1)wherein R¹ is a hydrogen atom, namely a compound of the formula (6):

wherein R⁵ represents a halogen atom, C1–C4 alkyl group or C1–C4fluoroalkyl group;can be easily produced by reacting a compound of the formula (5):

wherein X represents a halogen atom and R⁵ represents the same meaningmentioned above,with hydrogen for dehalogenation in the presence of a hydrogenationcatalyst and base in a solvent.

A catalyst having an efficacy reducing aromatic halides, such as noblemetal catalyst including palladium catalyst and platinum catalyst, isused as the hydrogenation catalyst. In particular, preferable is acatalyst supported a noble metal such as palladium and platinum on acarrier such as silica gel, alumina, activated carbon, diatomaceousearth and calcium carbonate. In that case, the amount of the supportednoble metal is usually 0.1–50 parts by weight, preferably 1–10 parts byweight per 100 parts by weight of the carrier. Further, the amount ofthe hydrogenation catalyst is usually 0.1–100 parts by weight,preferably 1–50 parts by weight per 100 parts by weight of the compoundof the formula (5).

The bases used for the reaction are inorganic bases such as alkalihydroxide (e.g. potassium hydroxide, sodium hydroxide), alkaline earthhydroxide (e.g. barium hydroxide), alkaline earth oxide (e.g. magnesiumoxide, calcium oxide), alkali acetate (e.g. sodium acetate, potassiumacetate) and ammonia, and organic bases such as triethylamine. Theamount of the base used in the reaction is usually between 1 and 20moles, preferably between 1 and 5 moles per 1 mole of the compound ofthe formula (5).

As the solvent used for the reaction, water, alcohols and mixturesthereof are preferable. Among the alcohols, C1–C4 alcohol such asmethanol, ethanol, propanol, isopropyl alcohol, butanol and sec-butylalcohol is preferable. The amount of the solvent used for the reactionis usually between 1 and 100 parts by weight, preferably between 1 and10 parts by weight per 1 part by weight of the compound of the formula(5). The reaction is carried out with or without pressure, usually atatmospheric pressure to 10 MPa, preferably at atmospheric pressure to1.0 Mpa. The reaction temperature is usually 0 to 150° C., preferably 20to 60° C.

The dihydroxy(3-pyridyl)borane compounds of the formula (1) can beisolated from the reaction mixture by conventional procedures such asfiltration, neutralization, extract, concentration, distillation,recrystallization and/or column chromatography.

The dihydroxy(3-pyridyl)borane compound of the present invention readilychanges to its anhydride under heating or the like. Namely, it readilychanges to a boroxine compound of the formula (7):

[wherein Ar represents a 3-pyridyl group of the formula:

wherein R¹ and R² represent the same meanings mentioned above] byintermolecular dehydration-condensation. This boroxine compound can beeasily derived to pyridine compounds having an aromatic hydrocarbylgroup or aromatic heterocyclic group at 3-position as well as thedihydroxy(3-pyridyl)borane compound of the present invention.

Typical examples of the dihydroxy(3-pyridyl)borane compound of theformula (1) of the present invention includedihydroxy(2-chloro-3-pyridyl)borane, dihydroxy(2-bromo-3-pyridyl)borane,dihydroxy(2,5-dichloro-3-pyridyl)borane,dihydroxy(2-chloro-6-methyl-3-pyridyl)borane,dihydroxy(2-t-butoxycarbonylamino-3-pyridyl)borane anddihydroxy(2-chloro-5-trifluoromethyl-3-pyridyl)borane.

The dihydroxy(3-pyridyl)borane compound and its anhydride, boroxinecompound, of the present invention are, for example, derived tointermediates of medicaments, plant protectants and so on, organic ELmaterials and liquid crystal materials by coupling reaction with anaromatic halide. The coupling reaction can be, for example, performed inthe presence of palladium catalyst. It is usually carried out by using abase such as alkali carbonate and alkali hydroxide, triarylphosphinesuch as triphenylphosphine and palladium catalyst, in a solvent such aswater and alcohol, under heating at approximately 50 to 150° C.

EXAMPLES

Hereinafter, the present invention is more concretely explained byexamples, however, it should not be restricted by the examples below.

Example 1

A solution consisting of 2.11 ml (15 mmole) of diisopropylamine and 15ml of anhydrous tetrahydrofuran was cooled to 0° C., and 9.8 ml of 1.53mole/liter of n-butyllithium/hexane solution (15 mmole ofn-butyllithium) were added dropwise thereto over 10 minutes and stirredto give a mixture containing lithium diisopropylamide. The obtainedmixture was cooled to −78° C., and a solution consisting of 0.94 ml (10mmole) of 2-chloropyridine and 10 ml of anhydrous tetrahydrofuran wasadded dropwise thereto over 20 minutes and stirred at the sametemperature to allow to react for 2 hours. Further, a solutionconsisting of 1.14 ml (10 mmole) of trimethoxyborane and 10 ml ofanhydrous tetrahydrofuran was added dropwise thereto over 20 minutes andstirred at the same temperature to allow to react for 2 hours. To theresulted reaction mixture, 2.4 ml of hydrous tetrahydrofuran (watercontent: approximately 16% by weight) were added dropwise at −78° C.,and then allowed to stand to −10° C., and further 20 ml of water wereadded. The reaction mixture was allowed to stand at room temperature, towhich 20 ml of ethyl acetate were added and mixed. The water layer wasseparated from the organic layer, adjusted to about 4.0 of pH with 10%by weight of hydrochloric acid and extracted with 30 ml of ethyl acetatetwice. The ethyl acetate layers were combined, washed 20 ml of saturatedbrine, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography [eluent, ethyl acetate:acetic acid=100:0.1] to give 1.04g of reddish orange solid. The obtained solid is a mixture ofdihydroxy(2-chloro-3-pyridyl)borane and a compound having a boroxinestructure of the formula (4) which is its anhydride. The ¹H-NMR of themixture is as below. The yield was 66% calculated by converting todihydroxy(2-chloro-3-pyridyl)borane.

¹H-NMR (D₂O, NaOD, MeOD; ppm) σ: 8.09–8.15 (m, 1H), 8.06, 8.04, 7.98(each of these three peaks is dd, J=7.3 Hz, J=ca. 2.0 Hz, and the numberof the proton is totally 1H), 7.28 (ddd, J=6.8 Hz, J=4.8 Hz, J=1.6 Hz,1H)

Example 2

The same procedure as Example 1 except that 1.58 g (10 mmole) of2-bromopyridine were used in place of 2-chloropyridine was performed togive 1.55 g of brown solid. The obtained solid is a mixture ofdihydroxy(2-bromo-3-pyridyl)borane and a compound having a boroxinestructure of the formula (4) which is its anhydride. The ¹H-NMR of themixture is as below. The yield was 77% calculated by converting todihydroxy(2-bromo-3-pyridyl)borane.

¹H-NMR (D₂O, NaOD, MeOD; ppm) σ: 7.97–8.13 (m, 2H), 7.28–7.37 (m, 1H)

Example 3

The same procedure as Example 1 except that 1.28 g (10 mmole) of2-chloro-6-methylpyridine were used in place of 2-chloropyridine andthat 2.30 ml (10 mmole) of triisopropoxyborane were used in place oftrimethoxyborane was performed to give 480 mg of yellow solid. Theobtained solid is a mixture ofdihydroxy(2-chloro-6-methyl-3-pyridyl)borane and a compound having aboroxine structure of the formula (4) which is its anhydride. The ¹H-NMRof the mixture is as below. The yield was 28% calculated by convertingto dihydroxy(2-chloro-6-methyl-3-pyridyl)borane.

¹H-NMR (D₂O, NaOD, MeOD; ppm) σ: 7.84–7.98 (m, 1H), 7.13 (dd, J=7.3 Hz,J=1.8 Hz, 1H), 2.40 (s, 3H)

Example 4

The same procedure as Example 1 except that 1.82 g (10 mmole) of2-chloro-5-trifluoromethylpyridine were used in place of2-chloropyridine was performed to give 572 mg of brown solid. Theobtained solid is a mixture ofdihydroxy(2-chloro-5-trifluoromethyl-3-pyridyl)borane and a compoundhaving a boroxine structure of the formula (4) which is its anhydride.The ¹H-NMR of the mixture is as below. The yield was 25% calculated byconverting to dihydroxy(2-chloro-5-trifluoromethyl-3-pyridyl)borane.

¹H-NMR (D₂O, NaOD, MeOD; ppm) σ: 8.45–8.51 (m, 1H), 8.39, 8.36, 8.29(each of these three peaks is d, J=2.5 Hz, and the number of the protonis totally 1H)

Example 5

The same procedure as Example 1 except that 1.48 g (10 mmole) of2,5-dichloropyridine were used in place of 2-chloropyridine wasperformed to give 770 mg of pale yellow solid. The obtained solid is amixture of dihydroxy(2,5-dichloro-3-pyridyl)borane and a compound havinga boroxine structure of the formula (4) which is its anhydride. The¹H-NMR of the mixture is as below. The yield was 40% calculated byconverting to dihydroxy(2,5-dichloro-3-pyridyl)borane.

¹H-NMR (D₂O, NaOD, MeOD; ppm) σ: 8.15 (s, 1H), 7.65, 7.62, 7.57 (each ofthese three peaks is s, and the number of the proton is totally 1H)

Example 6

The same procedure as Example 1 except that 1.94 g (10 mmole) of2-butoxycarbonylaminopyridine were used in place of 2-chloropyridine wasperformed to give 47 mg of white solid. The obtained solid is a mixtureof (2-butoxycarbonylamino-3-pyridyl)borane and a compound having aboroxine structure of the formula (4) which is its anhydride. The ¹H-NMRof the mixture is as below. The yield was 2.0% calculated by convertingto dihydroxy(2-butoxycarbonylamino-3-pyridyl)borane.

¹H-NMR (D₂O, NaOD, MeOD; ppm) σ: 8.24 (m, 1H), 7.81 (m, 1H), 7.67 (d,J=8.4 Hz, 1H), 7.11 (ddd, J=6.5, J=5.3, J=0.8 Hz, 1H), 1.55 (s, 1H)

INDUSTRIAL APPLICABILITY

The dihydroxy(3-pyridyl)borane compounds of the present invention areuseful intermediates for producing pyridine compounds, having anaromatic hydrocarbyl group or aromatic heterocyclic group at 3-position,which are important intermediates for producing medicaments, plantprotectants and so on.

1. A dihydroxy(3-pyridyl)borane compound of the formula (1):

wherein R¹ represents a chlorine atom or alkoxycarbonylamino group; R²represents a hydrogen atom or alkyl group; the carbon number of thealkoxy in said alkoxycarbonylamino group being 1 to 4, and the carbonnumber of said alkyl group being 1 to 4; or an anhydride thereof.
 2. Thedihydroxy(3-pyridyl)borane compound according to claim 1, wherein R¹represents a chlorine atom; and R² represents a hydrogen atom or alkylgroup; or an anhydride thereof.
 3. The dihydroxy(3-pyridyl)boranecompound according to claim 1, wherein R¹ represents analkoxycarbonylamino group; and R² represents a hydrogen atom; or ananhydride thereof.
 4. A method for producing adihydroxy(3-pyridyl)borane compound, of the formula (1):

wherein R¹ represents a chlorine atom or alkoxycarbonylamino group; R²represents a hydrogen atom or alkyl group; the carbon number of thealkoxy in said alkoxycarbonylamino group being 1 to 4, and the carbonnumber of said alkyl group being 1 to 4; or an anhydride thereof, whichcomprises reacting a pyridine compound of the formula (2):

wherein R² represents a hydrogen atom or alkyl group; and R³ representsa chlorine atom or alkoxycarbonylamino group; the carbon number of thealkoxy in said alkoxycarbonylamino group being 1 to 4, with a lithiumamide in an organic solvent, reacting the reaction mixture with atrialkoxyborane compound of the formula (3):B(OR⁴)₃  (3) wherein R¹ represents an alkyl group, and then reacting theresultant reaction mixture with water.
 5. The method for producing adihydroxy(3-pyridyl)borane compound of the formula (6):

wherein R⁵ represents a halogen atom, alkyl group or fluoroalkyl group,each of the carbon number of said alkyl group is and said fluoroalkylgroup being 1 to 4, or an anhydride thereof, which comprises reacting adihydroxy(3-pyridyl)borane compound of the formula (5),

wherein X represents a halogen atom; and R⁵ has the same meaning asrecited above, with hydrogen in the presence of a hydrogenation catalystand a base in a solvent.
 6. The dihydroxy(3-pyridyl)borane compoundaccording to claim 1, wherein R¹ represents an alkoxycarbonylaminogroup; R2 represents a hydrogen atom or alkyl group, the carbon numberof the alkoxy in said alkoxycarbonylamino group is 1 to 4, and thecarbon number of said alkyl group is 1 to 4; or an anhydride thereof.